The American and Australian populations and indeed most of the developed world are facing an obesity epidemic; associated with this is a dramatic increase in the incidence of type 2 diabetes and its precursor, impaired glucose tolerance (IGT). In America approximately 24 million people (7.8% of the population) have diabetes with over 5 million of those undiagnosed. Australia does not fare much better and, if the current rates of mortality and diabetes incidence continue, the prevalence of diabetes is projected to rise from 7.6% in 2000 to 11.4% by 2025. More than a third of individuals will develop diabetes within their lifetime and in Australia there will an additional 1 million cases of diabetes by the year 2025. Early detection of diabetes or the identification of those at increased risk provides the opportunity for early treatment to prevent onset or progression of the disease. Obesity is an important risk factor for diabetes; however, not all obese individuals will go on to develop diabetes. Improved predictive markers are required. Altered lipid metabolism plays a key role in the development and progression of diabetes. However, the metabolic and signaling pathways involved are poorly defined. We hypothesise that dyslipidemia precedes the onset of type 2 diabetes, that the altered lipid metabolism will be reflected in the plasma lipid profile and that these profiles can be used as a clinical marker for the risk of disease onset and progression. We propose a novel lipidomic approach to characterise the dyslipidemia associated with the different stages of IGT and diabetes. We will then determine which aspects of the dyslipidemia precede the onset of disease and develop predictive models for the early identification of those individuals at increased risk of developing diabetes. We will validate this tool using existing plasma samples collected from longitudinal studies of well-characterised populations. We will also use the same lipidomic tools, combined with existing genetic data, to define the molecular mechanisms that perturb lipid homeostasis contributing to disease onset and progression. The specific aims are to: 1) Characterise the differences in the plasma lipid profile associated with IGT and diabetes and develop models to classify patients. 2) Determine the plasma lipid profiles that precede the onset of diabetes and develop predictive models to identify individuals at increased risk of developing diabetes. 3) Validate plasma lipid profiling for prediction of the onset of diabetes through retrospective analysis of longitudinal studies on clinically defined populations. 4) Define molecular mechanisms that control lipid homeostasis and diabetes risk by combining metabolomic and genomic analysis of a large multi-family cohort. This novel approach will provide a rapid, inexpensive but highly predictive screening tool that will form an important part of the ongoing development of risk stratification and patient management for individuals at risk of developing diabetes. The cost of such a test would be comparable with other routine pathology tests such as blood glucose or cholesterol, based on an analytical cost of approximately US$10. Mapping the molecular mechanisms and pathways of disease pathogenesis using our combined metabolomic and genomic databases will improve our understanding of these processes and facilitate the development and refinement of our predictive models. PUBLIC HEALTH RELEVANCE: The American and Australian populations and indeed most of the developed world are facing an obesity epidemic; associated with this is a dramatic increase in the incidence of type 2 diabetes and its precursor, impaired glucose tolerance (IGT). In America approximately 23.6 million people (7.8% of the population) have diabetes with over 5 million of those undiagnosed. Australia does not fare much better and if the current rates of mortality and diabetes incidence continue the prevalence of diabetes is projected to rise from 7.6% in 2000 to 11.4% by 2025. More than a third of individuals will develop diabetes within their lifetime and in Australia there will an additional 1 million cases of diabetes by the year 2025. Early detection of diabetes or the identification of those at increased risk provides the opportunity for early treatment to prevent onset or progression of the disease. This project will develop a rapid, inexpensive (AUD$10) but highly predictive screening tool that will form an important part of the ongoing development of risk stratification and patient management for individuals at risk of developing type 2 diabetes.